Hydroxamic and carboxylic acid derivatives

ABSTRACT

Pharmacologically active compounds are provided as well as pharmaceutical compositions and methods for treating cancer; inflammation; an autoimmune, infectious or ocular disease; or age-related macular degeneration in a mammal.

FIELD OF THE INVENTION

This invention relates to hydroxamic and carboxylic acid derivatives,and to their use in medicine.

BACKGROUND OF THE INVENTION

Metalloproteinases, including matrix metalloproteinase (MMP),collagenase, gelatinase and TNFα convertase (TACE), and their modes ofaction, and also inhibitors thereof and their clinical effects, aredescribed in WO-A-96/11209, WO-A-97/12902 and WO-A-97/19075, thecontents of which are incorporated herein by reference. MMP inhibitorsmay also be useful in the inhibition of other mammalianmetalloproteinases such as the ADAM or ADAM-TS families.

Compounds which have the property of inhibiting the action ofmetalloproteinases involved in connective tissue breakdown, such ascollagenase, stromelysin and gelatinase, have been shown to inhibit therelease of TNFα both in vitro and in vivo. See Gearing et al (1994),Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561;GB-A-2268934; and WO-A-93/20047. All of these reported inhibitorscontain a hydroxamic acid zinc-binding group, as do theimidazole-substituted compounds disclosed in WO-A-95/23790. Othercompounds that inhibit MMP and/or TNFαare described in WO-A-95/13289,WO-A-96/11209, WO-A-96/035687, WO-A-96/035711, WO-A-96/035712 andWO-A-96/035714.

SUMMARY OF THE INVENTION

The invention encompasses novel compounds of formula (I) which areinhibitors of matrix metalloproteinase, ADAM or ADAM-TS enzymes, andwhich are useful for the treatment of diseases mediated by those enzymesand/or TNFα-mediated diseases, including degenerative diseases andcertain cancers.

Novel compounds according to a first aspect of the invention arerepresented by formula (I):

wherein

R¹ is OH or NHOH;

R² is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo orheterocycloalkyl (any of which may be optionally substituted with one ormore substituents selected from R⁶, W and WR⁶); and

R³ is H or alkyl;

or R², R³ and the carbon atom to which they are attached togetherrepresent a carbocyclic or heterocyclic ring (either of which may besubstituted with one or more substituents selected from R⁶, W and WR⁶);

R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰, S(O)_(q)R¹⁰ where q is 0, 1or 2, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸; two R⁴ substituents may be attachedto the same carbon atom to form C(R⁴)₂, where each R⁴ may be the same ordifferent, and C(R⁴)₂ may represent C═O;

R⁵ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, CF₃, OR⁹, COR¹⁰,S(O)_(q)R¹⁰, CO₂R¹⁴, CONR⁷R⁸, S(O)_(q)NR⁷R⁸, halogen, NR¹⁰R¹¹ or CN, ortwo adjacent R⁵ substituents may be combined to form a heterocyclicring;

R⁶ is OR⁹, COR¹⁰, CO₂R¹⁵, CONR⁷R⁸, NR¹⁰R¹¹, S(O)_(q)R¹⁰, S(O)_(q)NR⁷R⁸,═O, ═NOR¹⁰, succinimido or the group

R⁷ and R⁸, which may be the same or different, are each H, alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl,heterocycloalkyl or cycloalkylalkyl, or R⁷ and R⁸ and the nitrogen towhich they are attached together represent a heterocyclic ring;

R⁹ is H, alkyl, CF₃, CHF₂, CH₂F, cycloalkyl, aryl, heteroaryl,heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl orcycloalkylalkyl;

R¹⁰ is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and

R¹¹ is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR¹², CONR⁷R⁸,S(O)_(q)R¹² or S(O)_(q)NR⁷R⁸;

or R¹⁰ and R¹¹ and the nitrogen to which they are attached togetherrepresent a heterocyclic ring;

R¹² is OR⁹ or R¹³;

R¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl;

R¹⁴ is H, alkyl or cycloalkyl;

R¹⁵ is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;

R¹⁶ is H or alkyl;

A is aryl or heteroaryl, provided that when A is phenyl, R³ is H;

W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclo or heterocycloalkyl;

each k and m is independently 0, 1, 2 or 3;

n is 0, 1 or 2; and

p is 0, 1 or 2;

or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxyor protected hydroxamic acid derivative thereof.

DESCRIPTION OF THE INVENTION

It will be appreciated that the compounds according to the invention cancontain one or more asymmetrically substituted carbon atoms. Thepresence of one or more of these asymmetric centres in a compound offormula (I) can give rise to stereoisomers, and in each case theinvention is to be understood to extend to all such stereoisomers,including enantiomers and diastereomers, and mixtures including racemicmixtures thereof

It will further be appreciated that the compounds according to theinvention may contain an oxime. This oxime can give rise to geometricalisomers, and in each case the invention is to be understood to extend toall such isomers and mixtures thereof

As used in this specification, alone or in combination, the term “alkyl”refers to straight or branched chain alkyl moiety having from one to sixcarbon atoms, including for example, methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, pentyl, hexyl and the like.

The term “alkenyl” refers to a straight or branched chain alkyl moietyhaving two to six carbon atoms and having in addition one double bond,of either E or Z stereochemistry where applicable. The term alkenylincludes for example, vinyl, 1-propenyl, 1- and 2- butenyl, 2-methyl-2-propenyl and the like.

The term “alkynyl” refers to a straight or branched chain alkyl moietyhaving two to six carbon atoms and having in addition one triple bond.The term alkynyl includes for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 1- methyl-2-butynyl and the like.

Cycloalkyl or carbocyclic ring refers to a non-aromatic cyclic ormulticyclic, saturated or partially saturated ring system having fromthree to ten carbon atoms which may be optionally benzofused at anyavailable position. Thus cycloalkyl includes, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,tetrahydronaphthyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1 ]heptenyl,cyclopentenyl, indanyl and the like.

Heterocyclo or heterocyclic ring refers to a 3 to 10 membered saturatedor partially saturated monocyclic or saturated or partially saturatedmulticyclic hydrocarbon ring system in which one or more of the atoms inthe ring system is an element other than carbon, chosen from amongstnitrogen, oxygen or sulphur (or oxidised versions thereof, such asN-oxide, sulphoxide, sulphone). Examples include azetidinyl,pyrrolidinyl, tetrahydrofuryl, piperidinyl, quinuclidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl,N-alkyl-piperazinyl, homopiperazinyl, oxazolidinyl, imidazolidinyl,thiazolidinyl, pyrazolidinyl, benzodioxole, [2,3-dihydro]benzofuryl,[3,4-dihydro]benzopyranyl, 1,2,3,4 tetrahydroquinolinyl, 1,2,3,4tetrahydroisoquinolinyl, 8-oxabicyclo[3.2.1]octane, indolinyl,isoindolinyl, and the like.

Aryl indicates carbocyclic radicals containing 6 to 10 carbon atoms andcontaining either a single ring or two condensed rings. Thus arylincludes, for example, phenyl and naphthyl.

Heteroaryl refers to a 5 to 10 membered aromatic monocyclic ormulticyclic hydrocarbon ring system in which one or more of the atoms inthe ring system is an element other than carbon, chosen from amongstnitrogen, oxygen or sulphur (or oxidised versions thereof, such asN-oxide). In general, the heteroaryl groups may be for examplemonocyclic or bicyclic fused ring heteroaryl groups. Monocyclicheteroaryl groups include, for example, five- or six-membered heteroarylgroups containing one, two, three or four heteroatoms selected fromoxygen, sulphur or nitrogen atoms. Bicyclic heteroaryl groups includefor example eight- to ten-membered fused-ring heteroaryl groupscontaining one, two or more heteroatoms selected from oxygen, sulphur ornitrogen atoms.

The term heteroaryl includes, for example, pyrrolyl, furyl, thienyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, pyridyl,pyridyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, benzothienyl,benzotriazolyl, indolyl, isoindolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl,benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolinyl, isoquinolinyl, phthalazinyl, tetrazolyl and the like.

Arylalkyl includes an aryl-alkyl- group wherein the aryl and alkyl areas described herein. Heteroarylalkyl includes a heteroaryl-alkyl- group,cycloalkylalkyl includes a cycloalkyl-alkyl- group and heterocycloalkylincludes a heterocyclo-alkyl- group, wherein all groups are as definedabove.

The term “halogen” includes fluorine, chlorine, bromine or iodine.

The term “benzofused” means the addition of a benzene ring sharing acommon bond with the defined ring system.

The term “optionally substituted” means optionally substituted by one ormore of the groups specified, at any available position or positions.

The terms “protected amino”, “protected carboxy” and “protectedhydroxamic acid” mean amino, carboxy and hydroxamic acid groups whichcan be protected in a manner familiar to those skilled in the art. Forexample, an amino group can be protected by a benzyloxycarbonyl,tert-butoxycarbonyl, acetyl or like group, or may be in the form of aphthalimido or like group. A carboxyl group can be protected in the formof a readily-cleavable ester such as the methyl, ethyl, benzyl ortert-butyl ester. A hydroxamic acid may be protected as either N orO-substituted derivatives, such as O-benzyl orO-tert-butyldimethylsilyl.

Salts of compounds of formula (I) or formula (II) includepharmaceutically-acceptable salts, for example acid addition saltsderived from inorganic or organic acids, such as hydrochlorides,hydrobromides, p-toluenesulphonates, phosphates, sulphates,perchlorates, acetates, trifluoroacetates, propionates, citrates,malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts may also be formed with bases. Such salts include salts derivedfrom inorganic or organic bases, for example alkali metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts.

When the “protected carboxy” group in compounds of the invention is anesterified carboxyl group, it may be a metabolically-labile ester offormula CO₂R where R may be an ethyl, benzyl, phenethyl, phenylpropyl, αor β-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl,2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl,2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl orpivaloylmethyl group.

Preferred compounds of the invention are those wherein any one or moreof the following may apply:

One group of compounds of the invention has the formula (I) in which R¹is NHOH.

In one preferred group of compounds of formula (I) R² is in particularisopropyl or isobutyl, especially isopropyl.

Another preferred group of compounds of formula (I) is where R² is asubstituted alkyl group, especially substituted methyl, ethyl or propyl.R² in compounds of this type is preferably substituted by R⁶, where R⁶is especially CO₂R¹⁵, in particular CO₂H, CONR⁷R⁸, NR¹⁰R¹¹, succinimidoor the group

In compounds of this type CONR⁷R⁸ is in particular CON(H)₂, CON(H)alkyl,CON(alkyl)₂ or R⁷ and R⁸ are attached together to form a heterocyclicring. NR¹⁰R¹¹ in compounds ofthis type is especially N(H)COR¹² orN(alkyl)COR¹², particularly preferred is where R¹² is alkyl. Each R¹⁶ incompounds of the invention is in particular methyl.

A further preferred group of compounds ofthe invention has the formula(I) where R² is an optionally substituted cycloalkyl or heterocyclogroup, especially an optionally substituted heterocyclo group. Incompounds of this type R² is in particular azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, tetrahydrofuryl or tetrahydropyranyl,especially optionally substituted piperidinyl. When substitutedcompounds of this type may in particular be substituted by R⁶,especially where R⁶ is CO₂R¹⁵. R¹⁵ may in particular be arylalkyl orheteroarylalkyl, preferably arylalkyl, especially benzyl.

R³ in compounds of the invention may in particular be a hydrogen atom.

One group of compounds of the invention has the formula (I) in which R²,R³ and the carbon atom to which they are attached together represent anoptionally substituted carbocylic or heterocyclic ring. Especiallypreferred compounds in this group are those where CR²R³ is a cycloalkylor a heterocyclic ring, in particular, C₃₋₇ cycloalkyl groups,especially, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups,and C₃₋₇ heterocyclo groups, especially, azetidinyl, pyrrolidinyl,tetrahydrofuryl, tetrahydropyranyl, piperidinyl and piperazinyl. Incompounds of this type CR²R³ is in particular cyclobutyl, cyclopentyl,cyclohexyl or tetrahydropyranyl.

Especially preferred is where p=1 and n=1.

In compounds of the invention k is preferably 0.

R⁵, when present may in particular be C₃₋₇ cycloalkyl, aryl, monocyclicheteroaryl, C₃₋₇ heterocyclo, CF₃, OR⁹, CONR⁷R⁸, F, Cl, Br, I or CN.Especially preferred is where R⁵ is cyclobutyl, cyclopentyl, cyclohexyl,phenyl, CF₃, OCH₃, OCF₃, OCHF₂, OCH₂F, CONH₂, CONHCH₃, CON(CH₃)₂, CN, F,Cl, Br or I. In compounds where R⁵ is present m is preferably 1 or 2.

One particular group of compounds of interest is represented by theformula (Ia):

wherein R¹, R², R⁴, R⁵, k and m, n and p are as previously described. Incompounds of formula (Ia) R³ is a hydrogen atom.

Another group of compounds has the formula (I) wherein A is inparticular pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl or 1,2,3-triazinyl,especially thiazolyl.

Particularly preferred compounds of the invention are:

1-[2-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoyl-ethyl]-piperidine-1-carboxylicacid benzyl ester;

2-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methyl-butyramide;

N-Hydroxy-3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyramide;

2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methyl-butyramide;

N-Hydroxy-3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)-butyramide;

and the salts, solvates, hydrates, N-oxides, protected amino, protectedcarboxy and protected hydroxamic acid derivatives thereof.

Compounds of the general formula (I) may be prepared by any suitablemethod known in the art and/or by the following processes.

It will be appreciated that, where a particular stereoisomer of formula(I) is required, the synthetic processes described herein may be usedwith the appropriate homochiral starting material and/or isomers mayberesolved from mixtures using conventional separation techniques (e.g.HPLC).

The compounds according to the invention may be prepared by thefollowing process. In the description and formulae below, the variousgroups R and other variables are as defined above, except whereotherwise indicated. It will be appreciated that functional groups, suchas amino, hydroxyl or carboxyl groups, present in the various compoundsdescribed below, and which it is desired to retain, may need to be inprotected form before any reaction is initiated. In such instances,removal of the protecting group may be the final step in a particularreaction. Suitable protecting groups for such functionality will beapparent to those skilled in the art. For specific details see Greene etal, “Protective Groups in Organic Synthesis”, Wiley Interscience (1999).

Thus, for example, compounds of the invention may be prepared by thefollowing general route:

Compounds of formula (IV), where W is for example an alkoxy group, suchas methoxy, ethoxy or tert-butoxy or a chiral auxiliary, for example,4-(R)-benzyloxazolidin-2-one, may be prepared by methods well known inthe literature, for example, by reaction of a sulfonyl chloride (II)with an amine (III) in the presence of an amine base, such astriethylamine in a halogenated solvent, such as dichloromethane at roomtemperature.

Compounds of general formula (II) are either known or may be made by oneskilled in the art using methods known in the literature, see forexample WO-A-99/24399, or as described in the examples herein after.Compounds of general formula (III) are available commercially or they bemade using methods known in the literature or by any method known tothose skilled in the art. For example, an amine of general formula (III)may be prepared by selective hydrogenation of a heteroaryl group, suchas isoquinoline using for example a platinum catalyst under acidicconditions. Appropriate conditions may be platinum (IV) oxide in thepresence of concentrated hydrochloric acid in ethanol under a pressureof 690 kPa. Alternatively, an amine of formula (III) where A is aheteroaryl group such as thiazolyl or oxazolyl may be prepared byformation of such a heteroaryl group on a suitably functionalised aminering such as N-tert-butoxycarbonyl-protected piperidin-4-one using wellknown methods. For example, the piperidinone (V) may be α-halogenatedusing standard conditions, such as reaction of the ketone withtrimethylsilyl chloride and an amine base such as triethylamine inN,N-dimethylformamide at 70° C., followed by α-halogenation using, forexample, N,N-bromosuccinimide in a suitable solvent such asacetonitrile. The α-bromoketone (VI) may then be reacted with a suitableamide or thioamide, such as thiobenzamide in conditions such asN,N-dimethylformamide at 80° C., to form the desired heteroaryl ring, asillustrated in the scheme below:

Carboxylic acids of general formula (I) may be prepared by deprotectionof a suitably protected carboxylic acid of formula (IV). For example,where W is an alkoxy group, such as ethoxy, a base such as aqueouslithium hydroxide may be used, alternatively trifluoroacetic acid may beused when W is a tert-butyl group or in the case of a chiral auxiliarysuch as 4-(R)-benzyl-oxazolidin-2-one, lithium hydroxide/hydrogenperoxide may be used. Appropriate solvent and temperature conditionssuch as those described in the examples herein after may be used.

Compounds of formula (I) may also be prepared by interconversion ofother compounds of formula (I). Thus, for example, hydroxamic acids ofgeneral formula (I) may be prepared using conditions well known in theliterature. For example, treatment of acids of formula (I) with oxalylchloride in an inert solvent (such as dichloromethane) gives anintermediate acid chloride, which may or may not be isolated, but whichin turn is reacted with hydroxylamine at a suitable temperature such asroom temperature to give the desired hydroxamic acids (I). Alternativelyan acid of formula (I) maybe activated in situ using for example adiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, advantageously in the presence of a catalyst such as aN-hydroxy compound, e.g. N-hydroxybenzotriazole using suitableconditions, e.g. in N,N-dimethylformamide at −15° C., prior to thesubsequent addition of a suitably protected hydroxylamine such astert-butyldimethyl silyl hydroxylamine and warming to ambienttemperature. The protecting group maybe removed using appropriateconditions, such as water or tetrabutylammonium fluoride and acetic acidin tetrahydrofuran at 0° C., to yield the desired hydroxamic acids offormula (I).

Similarly, intermediates of any appropriate formula may be prepared bythe interconversion of other compounds of the same formula.

Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallization, or by formation of a salt if appropriate or possibleunder the circumstances.

The compounds according to the invention exhibit in vitro inhibitingactivities with respect to the stromelysin, collagenase, gelatinase,ADAM or ADAM-TS enzymes. Compounds according to the invention may alsoexhibit in vitro inhibition of membrane-shedding events known to bemediated by metalloproteinases, for example, α-APP, ACE, TGF-α, TNF-α,Fas ligand, selectins, TNFR-I, TNFR-II, CD30, Il-6R, CD43, CD44, CD16-I,CD16-II, Folate receptor, CD23, or IL-1RII.

The activity and selectivity of the compounds may be determined by useof the appropriate enzyme inhibition test, for example as described inExamples A-M of WO-A-98/05635, by the assay for the inhibition of CD23shedding described in WO-A-99/24399, or by the assay of TNF RI sheddingdescribed in WO-A-00/56704.

This invention also relates to a method of treatment for patients(including man and/or mammalian animals raised in the dairy, meat or furindustries or as pets) suffering from disorders or diseases which can beattributed to metalloproteinases.

Accordingly, the compounds of formula (I) can be used among other thingsin the treatment of osteoarthritis and rheumatoid arthritis, and indiseases and indications resulting from the over-expression of thesematrix metalloproteinases such as found in certain metastatic tumourcell lines.

As mentioned above, compounds of formula (I) are useful in human orveterinary medicine since they are active as inhibitors of TNF and MMPs.Accordingly in another aspect, this invention concerns:

a method of management (by which is meant treatment or prophylaxis) ofdisease or conditions mediated by TNF, MMPs, ADAM or ADAM-TS enzymes, inmammals, in particular in humans, which method comprises administeringto the mammal an effective, amount of a compound of formula (I) above,or a pharmaceutically acceptable salt thereof; and

a compound of formula (I) for use in human or veterinary medicine,particularly in the management (by which is meant treatment orprophylaxis) of diseases or conditions mediated by TNF, MMPs, ADAM orADAM-TS enzymes; and

the use of a compound of formula (I) in the preparation of an agent forthe management (by which is meant treatment or prophylaxis) of diseasesor conditions mediated by TNF, MMPs, ADAM or ADAM-TS enzymes.

The disease or conditions referred to above include inflammatorydiseases, autoimmune diseases, cancer, cardiovascular diseases anddiseases involving tissue breakdown. Appropriate diseases includerheumatoid arthritis, osteoarthritis, osteoporosis, neurodegeneration,Alzheimer's disease, stroke, vasculitis, Crohn's disease, ulcerativecolitis, multiple sclerosis, periodontitis, gingivitis and thoseinvolving tissue breakdown such as bone resorption, haemorrhage,coagulation, acute phase response, cachexia and anorexia, acuteinfections, bacterial infections, HIV infections, fever, shock states,graft versus host reactions, dermatological conditions, surgical woundhealing, psoriasis, atopic dermatitis, epidermolysis bullosa, tumourgrowth, angiogenesis and invasion by secondary metastases,ophthalmological disease, retinopathy, corneal ulceration, reperfusioninjury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis,eczema, anaphylaxis, restenosis, congestive heart failure,endometriosis, atherosclerosis, endosclerosis, aspirin-independentanti-thrombosis, systemic lupus erythematosus and solid organtransplant.

Compounds of formula (I) may also be useful in the treatment of pelvicinflammatory disease (PID), age-related macular degeneration andcancer-induced bone resorption. Further, they can be used in thetreatment of lung diseases, e.g. selected from cystic fibrosis, adultrespiratory distress syndrome (ARDS), emphysema, bronchitisobliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis(PIF), diffuse alveolar damage, pulmonary Langerhan's cellgranulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronicobstructive pulmonary disease (COPD).

Compounds of the invention are particularly of use in the treatment ofinflammatory diseases, autoimmune diseases and cancer. Thus, forexample, the compounds may be used in the treatment (includingprophylaxis) of graft versus host reactions, psoriasis, atopicdermatitis, rhinitis, eczema, systemic lupus erythematosus, solid organtransplant, cystic fibrosis, rheumatoid arthritis, osteoarthritis,osteoporosis, Crohn's Disease, ulcerative colitis, multiple sclerosis,periodontitis, bone resorption, bacterial infections, epidermolysisbullosa, tumour growth, angiogenesis, ophthalmological disease,retinopathy, asthma, emphysema, bronchitis, and chronic obstructivepulmonary disease (COPD).

For the treatment of all diseases and disorders previously indicated,the compounds of formula (I) may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques. Ocular injection, such asintravitreal, subtenons, subconjunctival, periocular and retrobulbar mayalso be used, as well as intraocular slow release devices and implants.In addition to the treatment of warm-blooded animals such as mice, rats,horses, cattle, sheep, dogs, cats etc, the compounds of the inventionare effective in the treatment of humans.

The pharmaceutical composition containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from sweeteningagents, flavouring agents, colouring agents and preserving agents inorder to provide pharmaceutically elegant and palatable preparations.Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. No. 4,256,108, U.S.Pat. No. 4,166,452 and U.S. Pat. No. 4,265,874, to form osmotictherapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere in the active ingredient is mixed with an inert solid diluent, forexample calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such a polyoxyethylene with partial esters derived from fattyacids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one ormore colouring agents, one or more flavouring agents, and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified, for example sweetening, flavouringand colouring agents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soya bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be in a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A compound of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc, containing a compound of the invention are employed. For thepurposes of this specification, topical application includes mouthwashesand gargles.

For topical ocular administration, pharmaceutically acceptablesolutions, suspensions or gels containing the compounds of formula (I)may be used. Solutions and suspensions may also be adapted forintra-vitreal or intra-cameral use.

Dosage levels of the order of from about 0.05 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 2.5 mg to about 7 g per patient perday). For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day (about 0.5 mg to about 3.5 g per patient perday).

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may vary fromabout 5 to about 95% of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of activeingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following Examples illustrate the invention.

The following abbreviations are used:

Boc-tert-butoxy carbonyl; DCM-dichloromethane DMF-N,N-dimethylformamideEtOAc-ethyl acetate MeOH-methanol NBS-N-bromosuccinimideTFA-trifluoroacetic acid

Intermediate 1

6-Cyclohexyl-1,2,3,4tetrahydro-isoquinoline

Platinum (IV) oxide (30 mg), then 12M hydrochloric acid (1.5 ml) wasadded to a solution of 6-phenyl-isoquinoline (1.52 g) in ethanol (30ml). The mixture was transferred to a Parr high pressure apparatus andcharged with hydrogen to a pressure of 50 psi. The reaction was stirredat room temperature for 3 h then recharged with hydrogen to 100 psi andleft to stir for 16 h. The mixture was then filtered, fresh platinumcatalyst and 12M hydrochloric acid added, and the Parr high pressureapparatus charged to 75 psi. The reaction was left to stir at roomtemperature for 16 h, after which a white crystalline solid was observedin the reaction mixture. Water was added to dissolve this solid and themixture filtered through celite, washing with 1:1 water-methanol (3×30ml). The methanol was removed under reduced pressure then the aqueousbasified with concentrated sodium hydroxide solution and extracted with2:1 diethyl ether-ethyl acetate (3×50 ml). The combined extracts werewashed with water (2×20 ml), saturated sodium bicarbonate (20 ml) andbrine (20 ml) then dried (Na₂SO₄), filtered and evaporated under reducedpressure. The residue was purified by chromatography (SiO₂, 93:6:1dichloromethane-methanol-ammonia, then a second column with 94:5:1dichloromethane-methanol-ammonia) to give the title compound (190 mg) asa mixture containing approximately 20% of a slightly higher runningproduct.

R_(f) 0.27 (94:5:1 dichloromethane-methanol-ammonia)

Intermediate 2

4 Benzenesulfonyloxy-piperidine-1-carboxylic acid benzyl ester

Triethylamine (17 ml) was added dropwise to a solution of benzyl4-hydroxy-1-piperidinecarboxylate (28.83 g) in dichloromethane (100 ml)at 0° C. and stirred for 15 minutes. Benzenesulfonyl chloride (14 ml)was added and the reaction allowed to stir at room temperature for 48 h.The mixture was washed with water (50 ml), saturated sodium bicarbonatesolution (50 ml), water (50 ml) and brine (50 ml) then dried (Na₂SO₄),filtered and evaporated under reduced pressure. The residue was purifiedby chromatography (SiO₂, 20% ethyl acetate in hexane to 30% ethylacetate in hexane) to give the title compound (31.88 g, 77%) as a whitecrystalline solid.

R_(f) 0.62 (5% methanol in dichloromethane)

Intermediate 3

2-(1-Benzyloxycarbonyl-piperidin-4 yl)-malonic acid

Sodium metal (3.2 g) was dissolved in ethanol (50 ml) under a nitrogenatmosphere at room temperature. A solution of diethyl malonate (56.4 ml)in ethanol (50 ml) was added dropwise, followed by a solution of4-benzenesulfonyloxy-piperidine-1-carboxylic acid benzyl ester (31.88 g)in ethanol (50 ml), also added dropwise. The mixture was heated toreflux for 16 h then the solvent was removed under reduced pressure. Theresidue was partitioned between water (100 ml) and diethyl ether (100ml) and the aqueous washed with further diethyl ether (60 ml). Thecombined organics were washed with 10% citric acid solution (50 ml),water (50 ml) and brine (50 ml). After drying (Na₂SO₄) and filtering thesolvent was removed under reduced pressure to leave a yellow liquid.Half of this crude diester was taken and dissolved in methanol (150 ml)and water (50 ml). Lithium hydroxide monohydrate (18.14 g) was addedslowly and the reaction left to stir at room temperature for 16 h thenthe methanol was removed under reduced pressure. The aqueous was washedwith diethyl ether (3×40 ml), acidified to pH=3 with citric acid andextracted with ethyl acetate (2×40 ml). The combined organics werewashed with water (2×40 ml) and brine (40 ml), dried (Na₂SO₄), filteredand evaporated under reduced pressure to give the title compound (8.29g, 56%) as a white crystalline solid.

R_(f) 0.47 (5% methanol in dichloromethane)

Intermediate 4

4-(1-Carboxy-vinyl)-piperidine-1-carboxylic acid benzyl ester

2-(1-Benzyloxycarbonyl-piperidin-4-yl)-malonic acid (18.06 g) wasdissolved in tetrahydrofuran (140 ml) and morpholine (4.95 ml) followedby acetic acid (6.43 ml) was added, forming a white precipitate.Formaldehyde (4.56 g) was added, causing the precipitate to disappear,and the mixture heated to reflux for 4 h. The solvent was evaporated,diethyl ether (50 ml) added and the mixture extracted with water (3×60ml). The aqueous was acidified to pH=3 with citric acid and extractedwith diethyl ether (3×30 ml). The combined organic extracts were washedwith water (40 ml) and brine (40 ml), dried (Na₂SO₄), filtered and thesolvent removed under reduced pressure to give the title compound (16.65g) as a mixture containing approximately 10% of the acid startingmaterial.

R_(f) 0.5 (5% methanol in dichloromethane)

Intermediate 5

4-(2-Acetylsulfanyl-1-carboxy-ethyl)-piperidine-1 carboxylic acid benzylester

4-(1-Carboxy-vinyl)-piperidine-1-carboxylic acid benzyl ester (15.6 g)was dissolved in thioacetic acid (15 ml) and heated to reflux for 3 h.The thioacetic acid was evaporated under reduced pressure and azeotropedwith 1:1 hexane-dichloromethane (4×30 ml) to give the title compound(20.32 g, 95%) as an orange oil.

R_(f) 0.28 (40% ethyl acetate in hexane)

Intermediate 6

4-(2-Acetylsulfanyl-1-tert-butoxycarbonyl-ethyl)-piperidine-1-carboxylicacid benzyl ester

Sulfuric acid (1.15Sml) was added slowly to a solution of4-(2-acetylsulfanyl-1-carboxy-ethyl)-piperidine-1-carboxylic acid benzylester (20.32 g) in dichloromethane (60 ml). The mixture was cooled in anacetone/dry ice bath and cooled isobutylene (60 ml) added. The mixturewas transferred to a Parr high pressure apparatus and left to stirovernight then washed with water (30 ml), saturated sodium bicarbonatesolution (30 ml) and brine (30 ml). After drying (Na₂SO₄) and filteringthe solvent was removed under reduced pressure and the residue purifiedby column chromatography (SiO₂, 20% ethyl acetate in hexane) to give thetitle compound (11.22 g, 60%) as an orange oil.

R_(f) 0.25 (20% ethyl acetate in hexane)

Intermediate 7

4-(1-tert-Butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylicacid benzyl ester

A solution of4-(2-acetylsulfanyl-1-tert-butoxycarbonyl-ethyl)-piperidine-1-carboxylicacid benzyl ester (1.01 g) in dichloromethane (25 ml) and water (25 ml)was cooled in ice. Chlorine gas (500 mg) was bubbled through thesolution over 10 minutes then the mixture was flushed with nitrogen gas.The mixture was washed with water (25 ml) and brine (25 ml), then dried(Na₂SO₄), filtered and the solvent removed under reduced pressure togive the title compound (920 mg, 86%) as a colourless oil.

R_(f) 0.48 (30% ethyl acetate in hexane)

Intermediate 8

4-[1-tert-Butoxycarbonyl-2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-ethyl]-piperidine-1-carboxylicacid benzyl ester

1,2,3,4-Tetrahydroisoquinoline (0.17 ml) was dissolved indichloromethane (40 ml) at room temperature under nitrogen.Triethylamine (0.19 ml) was added, followed by4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylicacid benzyl ester (500 mg) as a solution in dichloromethane (1.5 ml).The reaction was left to stir for 64 h then diluted with dichloromethane(60 ml), washed with 10% citric acid solution (2×50 ml), water (2×50ml), saturated sodium bicarbonate solution (2×50 ml) and brine (50 ml).The organic layer was then dried (MgSO₄), filtered and the solventremoved under reduced pressure to give the title compound (506 mg, 83%)as a yellow oil.

R_(f) 0.44 (50% ethyl acetate in heptane)

The following compounds were prepared as above.

Intermediate 9

3-Methyl-2-(6-phenyl-3-4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyricacid tert-butyl ester

From 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (293mg) and 6-phenyl-1,2,3,4-tetrahydro-isoquinoline (206 mg) to give, afterchromatography (SiO₂, 25% diethyl ether in hexane), the title compound(340 mg, 78%) as a white solid.

R_(f) 0.24 (25% diethyl ether in hexane)

Intermediate 10

2-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyricacid tert-butyl ester

From 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (263mg) and 6-cyclohexyl-1,2,3,4-tetrahydro-isoquinoline (190 mg) to give,after chromatography (SiO₂, 25% diethyl ether in hexane), the titlecompound (230 mg, 58%) as a colourless gum.

R_(f) 0.36 (25% diethyl ether in hexane)

Intermediate 11

1-tert-Butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine

Trimethylsilyl chloride (25 ml) and triethylamine (50 ml) were added toa stirred solution of N-Boc piperidinone (30 g) in DMF (40 ml) and themixture was heated at 70° C. for 16 h. The solution was cooled to roomtemperature and diluted with hexanes (300 ml), the solution was washedwith sodium bicarbonate solution (3×100 ml), dried (MgSO₄) andevaporated to give a colourless oil. The product was purified on silicaeluting with 10% ethyl acetate/hexanes to give the title compound ascolourless oil (25 g, 62%).

R_(f) 0.7 (20% EtOAc/hexanes)

Intermediate 12

1-tert-Butoxycarbonyl-3-bromopiperidin-4-one

NBS (1.4 g) was added to a solution of1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine(2 g) in acetonitrile and the mixture was stirred at room temperaturefor 30 minutes. The solution was diluted with ethyl acetate(50 ml) andwashed with water (50 ml), sodium bicarbonate solution (50 ml) and brine(50 ml), dried (MgSO₄) and evaporated to give the title compound as acolourless solid (1.8 g).

R_(f) 0.40 (20% EtOAc/hexanes)

Intermediate 13

2-Phenyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine

A solution of 1-tert-butoxycarbonyl-3-bromopiperidin-4-one (8 g) andthiobenzamide (3.4 g) in DMF was heated at 70 ° C. for 16 h, then cooledto room temperature. The solvent was evaporated in vacuo and the residuedissolved in water (100 ml) and washed with ether (100 ml), thenbasified with sodium hydroxide and extracted into ethyl acetate (3×100ml). The solvent was dried (MgSO₄) and evaporated to give the titlecompound as cream solid (2.81 g, 53% based on thiobenzamide used).

MS 217 (M+1)

EXAMPLE 1

3-Methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyricacid

Trifluoroacetic acid (5 ml) was added to a solution of3-methyl-2-(6-phenyl-3-4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyricacid tert-butyl ester (0.33 g) in dichloromethane (20 ml). The reactionwas stirred at room temperature for 4 h then evaporated under reducedpressure. Diethyl ether (10 ml) was added to the residue then extractedwith 1M sodium hydroxide solution. The aqueous was extracted withdiethyl ether (10 ml), acidified with citric acid to pH=3 then extractedwith ethyl acetate (3×10 ml). The combined ethyl acetate extracts werewashed with water (2×10 ml) and brine (10 ml), dried (Na₂SO₄), filteredand evaporated under reduced pressure to give the title compound (250mg, 87%) as a white solid.

R_(f) 0.26 (50% diethyl ether in hexane plus acetic acid) MS 388 (M+1),386 (M−1)

The following compound was prepared as above.

EXAMPLE 2

2-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyricacid

From 2-(6-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyric acid tert-butyl ester(230 mg) to give the title compound (164 mg, 82%) as a white solid.

R_(f) 0.27 (50% diethyl ether in hexane plus acetic acid) MS 394 (M+1),392 (M−1)

EXAMPLE 3

2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyricacid

2-Chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (1.0 ml ofa 1M solution in dichloromethane) was added to a solution of6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (230 mg) andtriethylamine (0.31 ml) in dichloromethane (10 ml) and the mixturestirred at room temperature for 16 h. Trifluoroacetic acid was added (5ml) and the reaction left to stir for 2 h then diluted with hexane (10ml) and evaporated under reduced pressure. The residue was azeotropedwith 1:1 dichloromethane-hexane (2×10 ml), dissolved in 1M sodiumhydroxide and washed with diethyl ether (2×10 ml). The aqueous wasacidified to pH=4 with citric acid and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with water (10 mil) and brine(10 ml), dried (Na2SO₄), filtered and evaporated under reduced pressureto give the title compound (93 mg, 25%).

R_(f) 0.43 (5% methanol in dichloromethane) MS (M+1) 372 and (M−1) 370

EXAMPLE 4

3-Methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)-butyricacid

2-Phenyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (0.11 g) was addedto a solution of 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butylester (0.14 g) and triethylamine (0.3 ml) in DCM (20 ml) at roomtemperature. The solution was stirred for 2 h, then TFA (5 ml) was addedand the mixture stirred for 1 h. The mixture was evaporated in vacuo andthe residue partitioned between diethyl ether (10 ml) and saturatedsodium bicarbonate (30 ml). The aqueous layer was acidified with citricacid to pH 5 and extracted with ethyl acetate (3×20 ml). The solvent wasdried (MgSO₄) and evaporated to give the title compound as pale yellowsolid (0.15 g).

R_(f) 0.32 (EtOAc)

EXAMPLE 5

1-[2-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoyl-ethyl]-piperidine-1-carboxylicacid benzyl ester

Trifluoroacetic acid (5.0 ml) was added to a solution of4-[1-tert-butoxycarbonyl-2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)ethyl]-piperidine-1-carboxylicacid benzyl ester (506 mg) in dichloromethane (30 ml). The reaction wasstirred at room temperature for 3.5 h then the solvent and excesstrifluoroacetic acid evaporated under reduced pressure to give thecarboxylic acid as a yellow solid. This was dissolved in dichloromethane(30 ml) under a nitrogen atmosphere and oxalyl chloride (0.1 ml) added,followed by N,N-dimethylformamide (a few drops, catalytic). The reactionwas left to stir for 16 h then evaporated under reduced pressure to givethe acid chloride as a yellow solid. This was suspended intetrahydrafuran (10 ml) and 50% wt solution of aqueous hydroxylamine(0.30 ml) was added. The reaction was left to stir at room temperaturefor 20 minutes then the solvent was evaporated under reduced pressure.The residue was triturated with water (20 ml), the resulting solidfiltered off and washed with water (10 ml). Purification by reversephase preparative HPLC using a 25 cm×21.4 mm Phenomenex Luna C18 (2) (5u) column and a mobile phase of aqueous trifluoroacetic acid (0.05% v/v)and acetonitrile under gradient conditions from 20% to 70% acetonitrilegave the title compound (83 mg, 18%) as a pale yellow solid, >98% pureby HPLC analysis.

R_(f) 0.18 (5% methanol in dichloromethane) MS 500 (M−1)

EXAMPLE 6

2-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methyl-butyramide

2-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyricacid (143 mg) was dissolved in dichloromethane (15 ml) under a nitrogenatmosphere and oxalyl chloride (0.15 ml) added, followed by a solutionof 10% N,N-dimethylformamide in dichloromethane (7 drops). The reactionwas stirred at room temperature for 2 h then evaporated under reducedpressure and azeotroped with 1:1 dichloromethane-hexane (2×10 ml). Theresidue was dried under vacuum then suspended in tetrahydrofuran (15 ml)and treated with 50%wt solution of aqueous hydroxylamine (0.7 ml). Themixture was left to stir at room temperature for 1 h then evaporatedunder reduced pressure. The residue was triturated with water (20 ml)and the resulting solid filtered off, washed with water (10 ml) anddried under vacuum at 40° C. to give the title compound (120 mg, 82%).

R_(f) 0.32 (5% methanol in dichloromethane) MS 407 (M−1)

The following compounds were prepared as above.

EXAMPLE 7

N-Hydroxy-3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyramide

From3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyricacid (230 mg), to give the title compound (220 mg, 93%).

R_(f) 0.28 (5% methanol in dichloromethane) MS 403 (M+1)

EXAMPLE 8

2-(6,7-Dimethoxy-3,4dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methyl-butyramide

From2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyricacid (80 mg), to give the title compound (71 mg, 85%).

R_(f) 0.27 (5% methanol in dichloromethane) MS 387 (M+1)

EXAMPLE 9

N-Hydroxy-3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)-butyramide

From 3-methyl-2-(2-phenyl-6,7-dihydro-4 H-thiazolo[5,4-c]pyridine-5sulfonyl methyl)-butyric acid (0.15 g), to give the title compound asbeige solid (85 mg).

R_(f) 0.33 (7% MeOH/DCM) MS 409 (M+1)

We claim:
 1. A compound of formula (I)

wherein R¹ is OH or NHOH; R² is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclo or heterocycloalkyl (any of which may be optionallysubstituted with one or more substituents selected from R⁶, W and WR⁶);and R³ is H or alkyl; or R², R³ and the carbon atom to which they areattached together represent a carbocyclic or heterocyclic ring (eitherof which may be substituted with one or more substituents selected fromR⁶, W and WR⁶); R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰, S(O)_(q)R¹⁰where q is 0, 1 or 2, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸; two R⁴ substituentsmay be attached to the same carbon atom to form C(R⁴)₂, where each R⁴may be the same or different, and C(R⁴)₂ may represent C═O; R⁵ is alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, CF₃, OR⁹, COR¹⁰, S(O)_(q)R¹⁰,CO₂R¹⁴, CONR⁷R⁸, S(O)_(q)NR⁷R⁸, halogen, NR¹⁰R¹¹ or CN, or two adjacentR⁵ substituents may be combined to form a heterocyclic ring; R⁶ is OR⁹,COR¹⁰, CO₂R¹⁵, CONR⁷R⁸, NR¹⁰R¹¹, S(O)_(q)R¹⁰, S(O)_(q)NR⁷R⁸, =0, ═NOR¹⁰,succinimido or the group

R⁷ and R⁸, which may be the same or different, are each H, alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl,heterocycloalkyl or cycloalkylalkyl, or R⁷ and R⁸ and the nitrogen towhich they are attached together represent a heterocyclic ring; R⁹ is H,alkyl, CF₃, CHF₂, CH₂F, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁰ isH, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and R¹¹ is H,alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR¹², CONR⁷R⁸,S(O)_(q)R¹² or S(O)_(q)NR⁷R⁸; or R¹⁰and R¹¹ and the nitrogen to whichthey are attached together represent a heterocyclic ring; R¹² is OR⁹ orR¹³; R¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁴ is H, alkyl orcycloalkyl; R¹⁵ is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;R¹⁶ is H or alkyl; A is aryl, provided that when A is phenyl, R³ is H; Wis alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclo or heterocycloalkyl; each k and m isindependently 0, 1, 2 or 3; n is 0 or 1; p is 0, 1 or 2; and p+n=2 or asalt, solvate, hydrate, N-oxide, protected amino, protected carboxy orprotected hydroxamic acid derivative thereof.
 2. The compound of claim1, wherein R¹ is NHOH.
 3. The compound of claim 1, wherein R⁴ is alkyl,cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰, S(O)_(q)R¹⁰, CONR⁷R⁸, CN orS(O)_(q)NR⁷R⁸, or C(R⁴)₂ is C═O; R⁶ is not succinimido or

when R⁶ is CO₂R¹⁵, R¹⁵ is H, alkyl or cycloalkyl; A is phenyl and R³ isH.
 4. The compound of claim 1, which is selected from3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)butyricacid,2-(6-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyricacid,2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyricacid,1-[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoylethyl]-piperidine-1-carboxylicacid benzyl ester,2-(6cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide,N-hydroxy-3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2sulfonylmethyl)-butyramide,and2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide.5. A pharmaceutical composition, comprising a compound of formula (I)

wherein R¹ is OH or NHOH; R² is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclo or heterocycloalkyl (any of which may be optionallysubstituted with one or more substituents selected from R⁶, W and WR⁶);and R³ is H or alkyl; or R², R³ and the carbon atom to which they areattached together represent a carbocyclic or heterocyclic ring (eitherof which may be substituted with one or more substituents selected fromR⁶, W and WR⁶); R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰, S(O)_(q)R¹⁰where q is 0, 1 or 2, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸; two R⁴ substituentsmay be attached to the same carbon atom to form C(R⁴)₂, where each R⁴may be the same or different, and C(R⁴)₂ may represent C═O; R⁵ is alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, CF₃, OR⁹, COR¹⁰, S(O)_(q)R¹⁰,CO₂R¹⁴, CONR⁷R⁸, S(O)_(q)NR⁷R⁸, halogen, NR¹⁰R¹¹ or CN, or two adjacentR⁵ substituents may be combined to form a heterocyclic ring; R⁶ is OR⁹,COR¹⁰, CO₂R¹⁵, CONR⁷R⁸, NR¹⁰R¹¹, S(O)_(q)R¹⁰, S(O)_(q)NR⁷R⁸, =0, ═NOR¹⁰,succinimido or the group

R⁷ and R^(8,) which may be the same or different, are each H, alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl,heterocycloalkyl or cycloalkylalkyl, or R⁷ and R⁸ and the nitrogen towhich they are attached together represent a heterocyclic ring; R⁹ is H,alkyl, CF₃, CHF₂, CH₂F, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁰ isH, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and R¹¹ is H,alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR¹², CONR⁷R⁸,S(O)_(q)R¹² or S(O)_(q)NR⁷R⁸; or R¹⁰ and R¹¹ and the nitrogen to whichthey are attached together represent a heterocyclic ring; R¹² is OR⁹ orR¹³; R¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁴ is H, alkyl orcycloalkyl; R¹⁵ is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;R¹⁶ is H or alkyl; A is aryl, provided that when A is phenyl, R³ is H; Wis alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclo or heterocycloalkyl; each k and m isindependently 0, 1, 2 or 3; n is 0 or 1; p is 0, 1 or 2; and p+n=2 or asalt, solvate, hydrate, N-oxide, protected amino, protected carboxy orprotected hydroxamic acid derivative thereof; and apharmaceutically-acceptable diluent or carrier.
 6. The pharmaceuticalcomposition, according to claim 5, wherein R¹ is NHOH.
 7. Thepharmaceutical composition, according to claim 5, wherein R⁴ is alkyl,cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰, S(O)_(q)R¹⁰, CONR⁷R⁸, CN orS(O)_(q)NR⁷R⁸, or C(R⁴)₂ is C═O; R⁶ is not succinimido or

when R⁶ is CO₂R¹⁵, R¹⁵ is H, alkyl or cycloalkyl; A is phenyl and R₃ isH.
 8. The pharmaceutical composition, according to claim 5, wherein saidcompound is selected from3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)butyricacid,2-(6-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyricacid,2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyricacid,1-[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoylethyl]-piperidine-1-carboxylicacid benzyl ester,2-(6cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide,N-hydroxy-3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2sulfonylmethyl)-butyramide,and2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl))-N-hydroxy-3-methylbutyramide.9. A method for the treatment of cancer; inflammation; an autoimmune,infectious or ocular disease; or age-related macular degeneration in amammal; wherein said method comprises administering to a patient in needof such treatment an effective amount of a compound of formula (I)

wherein R¹ is OH or NHOH; R² is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclo or heterocycloalkyl (any of which may be optionallysubstituted with one or more substituents selected from R⁶, W and WR⁶);and R³ is H or alkyl; or R², R³ and the carbon atom to which they areattached together represent a carbocyclic or heterocyclic ring (eitherof which may be substituted with one or more substituents selected fromR⁶, W and WR⁶); R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰, S(O)_(q)R¹⁰where q is 0, 1 or 2, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸; two R⁴ substituentsmay be attached to the same carbon atom to form C(R⁴)₂, where each R⁴may be the same or different, and C(R⁴)₂ may represent C═O; R⁵ is alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, CF₃, OR⁹, COR¹⁰, S(O)_(q)R¹⁰,CO₂R¹⁴, CONR⁷R⁸, S(O)_(q)NR⁷R⁸, halogen, NR¹⁰R¹¹ or CN, or two adjacentR⁵ substituents may be combined to form a heterocyclic ring; R⁶ is OR⁹,COR¹⁰, CO₂R¹⁵, CONR⁷R⁸, NR¹⁰R¹¹, S(O)_(q)R¹⁰, S(O)_(q)NR⁷R⁸, =0, ═NOR¹⁰,succinimido or the group

R⁷ and R⁸, which may be the same or different, are each H, alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl,heterocycloalkyl or cycloalkylalkyl, or R⁷ and R⁸ and the nitrogen towhich they are attached together represent a heterocyclic ring; R⁹ is H,alkyl, CF₃, CHF₂, CH₂F, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁰ isH, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and R¹¹ is H,alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR¹², CONR⁷R⁸,S(O)_(q)R¹² or S(O)_(q)NR⁷R⁸; or R¹⁰ and R¹¹ and the nitrogen to whichthey are attached together represent a heterocyclic ring; R¹² is OR⁹ orR¹³; R¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁴ is H, alkyl orcycloalkyl; R¹⁵ is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;R¹⁶ is H or alkyl; A is aryl, provided that when A is phenyl, R³ is H; Wis alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclo or heterocycloalkyl; each k and m isindependently 0, 1, 2 or 3; n is 0 or 1; p is 0, 1 or 2; and p+n=2 or asalt, solvate, hydrate, N-oxide, protected amino, protected carboxy orprotected hydroxamic acid derivative thereof.
 10. The method, accordingto claim 9, wherein R¹ is NHOH.
 11. The method, according to claim 9,wherein R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰, S(O)_(q)R¹⁰,CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸, or C(R⁴)₂ is C═O; R⁶ is not succinimido or

when R⁶ is CO₂R¹⁵, R¹⁵ is H, alkyl or cycloalkyl; A is phenyl and R³ isH.
 12. The method, according to claim 9, wherein said compound isselected from3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)butyricacid,2-(6-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyricacid,2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyricacid,1-[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoylethyl]-piperidine-1-carboxylicacid benzyl ester,2-(6-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide,N-hydroxy-3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyramide,and2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide.